-The effect of exercise-induced arterial hypoxemia (EIAH) on quadriceps muscle fatigue was assessed in 11 male endurance-trained subjects [peak O 2 uptake (V O2 peak) ϭ 56.4 Ϯ 2.8 ml⅐kg Ϫ1 ⅐min Ϫ1 ; mean Ϯ SE]. Subjects exercised on a cycle ergometer at Ն90% V O2 peak to exhaustion (13.2 Ϯ 0.8 min), during which time arterial O 2 saturation (SaO 2 ) fell from 97.7 Ϯ 0.1% at rest to 91.9 Ϯ 0.9% (range 84 -94%) at end exercise, primarily because of changes in blood pH (7.183 Ϯ 0.017) and body temperature (38.9 Ϯ 0.2°C). On a separate occasion, subjects repeated the exercise, for the same duration and at the same power output as before, but breathed gas mixtures [inspired O2 fraction (FIO 2 ) ϭ 0.25-0.31] that prevented EIAH (Sa O 2 ϭ 97-99%). Quadriceps muscle fatigue was assessed via supramaximal paired magnetic stimuli of the femoral nerve (1-100 Hz). Immediately after exercise at FI O 2 0.21, the mean force response across 1-100 Hz decreased 33 Ϯ 5% compared with only 15 Ϯ 5% when EIAH was prevented (P Ͻ 0.05). In a subgroup of four less fit subjects, who showed minimal EIAH at FIO 2 0.21 (SaO 2 ϭ 95.3 Ϯ 0.7%), the decrease in evoked force was exacerbated by 35% (P Ͻ 0.05) in response to further desaturation induced via FI O 2 0.17 (SaO 2 ϭ 87.8 Ϯ 0.5%) for the same duration and intensity of exercise. We conclude that the arterial O 2 desaturation that occurs in fit subjects during high-intensity exercise in normoxia (Ϫ6 Ϯ 1% ⌬Sa O 2 from rest) contributes significantly toward quadriceps muscle fatigue via a peripheral mechanism. magnetic stimulation; low-and high-frequency fatigue; quadriceps twitch force; voluntary activation; peripheral fatigue; central fatigue EXERCISE-INDUCED ARTERIAL HYPOXEMIA (EIAH), defined as a reduced arterial HbO 2 saturation below preexercise levels, occurs during sustained, heavy-intensity exercise to exhaustion in a significant number of healthy subjects (9). The desaturation is attributable primarily to a reduced arterial O 2 partial pressure (Pa O 2 ) in some highly fit subjects (17, 22, 52) or, more universally, to a rightward shift of the O 2 dissociation curve because of a time-and intensity-dependent metabolic acidosis and an increase in body temperature (42,50). EIAH has a detrimental effect on maximal O 2 uptake (V O 2 max ) (16, 41) and endurance exercise performance (36, 37).Multiple "peripheral" and "central" mechanisms have been proposed to explain how arterial hypoxemia limits endurance exercise performance. There is potential for reduced O 2 transport to cause limb muscle fatigue during heavy exercise via an effect of hypoxia on Ca 2ϩ uptake and Ca 2ϩ release by the sarcoplasmic reticulum (10). Changes in the intracellular environment may impair Ca 2ϩ cycling and other excitation/ contraction processes. Alternatively, an inability of the sarcolemma and T tubule to conduct repetitive action potentials may indirectly reduce Ca 2ϩ cycling. The possibility that such peripheral processes are involved in exercise limitation during hypoxemia is suggested by the finding that...